chr17-80210880-CG-C

Variant names:

• chr17-80210880-CG-C
• rs770947426
• NM_000199.5:c.1080delC

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PS3 PP5_Very_Strong

The NM_000199.5(SGSH):​c.1080delC​(p.Val361SerfsTer52) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,612,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000920205: At least two publications reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Montfort 2004, Heron 2010)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. T360T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SGSH NM_000199.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15 O:1
• Conservation: PhyloP100: -3.75
• Publications: 9 publications found

Genes affected

SGSH (HGNC:10818): (N-sulfoglucosamine sulfohydrolase) This gene encodes the enzyme sulfamidase; one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with the lysosomal storage disease mucopolysaccaridosis IIIA, also known as Sanfilippo syndrome A, which results from impaired degradation of heparan sulfate. Transcripts of varying sizes have been reported but their biological validity has not been determined. [provided by RefSeq, Jun 2017]

CARD14 (HGNC:16446): (caspase recruitment domain family member 14) This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

CARD14 Gene-Disease associations (from GenCC):

• familial pityriasis rubra pilaris

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• psoriasis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 66 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000920205: At least two publications reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Montfort 2004, Heron 2010).; SCV000929900: *"Low in vitro enzymatic acitivity."*; SCV001824491: Published functional studies of the c.1080delC variant demonstrate reduced enzyme activity (Montfort et al., 2004)
• PP5: Variant 17-80210880-CG-C is Pathogenic according to our data. Variant chr17-80210880-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 518268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000199.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSH	NM_000199.5	MANE Select	c.1080delC	p.Val361SerfsTer52	frameshift	Exon 8 of 8	NP_000190.1	P51688
	SGSH	NM_001352921.3		c.*167delC		3_prime_UTR	Exon 8 of 8	NP_001339850.1
	SGSH	NM_001352922.2		c.*130delC		3_prime_UTR	Exon 9 of 9	NP_001339851.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSH	ENST00000326317.11	TSL:1 MANE Select	c.1080delC	p.Val361SerfsTer52	frameshift	Exon 8 of 8	ENSP00000314606.6	P51688
	SGSH	ENST00000575282.5	TSL:1	n.3963delC		non_coding_transcript_exon	Exon 5 of 5
	SGSH	ENST00000874335.1		c.1116delC	p.Val373SerfsTer52	frameshift	Exon 9 of 9	ENSP00000544394.1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000721 AC: 18 AN: 249790 AF XY: 0.0000887

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000974

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000110 AC: 161 AN: 1460682 Hom.: 0 Cov.: 34 AF XY: 0.000127 AC XY: 92 AN XY: 726588

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.000134 AC: 6 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000137 AC: 152 AN: 1111972

Other (OTH) AF: 0.0000497 AC: 3 AN: 60374

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41552

American (AMR) AF: 0.000196 AC: 3 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000567

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Mucopolysaccharidosis, MPS-III-A (12)
3	-	-	not provided (3)
-	-	-	Mucopolysaccharidosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-3.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770947426; hg19: chr17-78184679; COSMIC: COSV108155248; COSMIC: COSV108155248;